title: Constitutive activation of the Nrf2/Keap1 pathway in insecticide-resistant strains of Drosophila.
abstract: Pesticide resistance poses a major challenge for the control of vector-borne human diseases and agricultural crop protection. Although a number of studies have defined how mutations in specific target proteins can lead to insecticide resistance, much less is known about the mechanisms by which constitutive overexpression of detoxifying enzymes contributes to metabolic pesticide resistance. Here we show that the Nrf2/Keap1 pathway is constitutively active in two laboratory-selected DDT-resistant strains of Drosophila, 91R and RDDTR, leading to the overexpression of multiple detoxifying genes. Disruption of the Drosophila Nrf2 ortholog, CncC, or overexpression of Keap1, is sufficient to block this transcriptional response. In addition, a CncC-responsive reporter is highly active in both DDT-resistant strains and this response is dependent on the presence of an intact CncC binding site in the promoter. Microarray analysis revealed that ∼20% of the genes differentially expressed in the 91R strain are known CncC target genes. Finally, we show that CncC is partially active in these strains, consistent with the fitness cost associated with constitutive activation of the pathway. This study demonstrates that the Nrf2/Keap1 pathway contributes to the widespread overexpression of detoxification genes in insecticide-resistant strains and raises the possibility that inhibitors of this pathway could provide effective synergists for insect population control.
authors.affiliation: Department of Human Genetics, University of Utah School of Medicine, 15 North 2030 East, Room 2100, Salt Lake City, UT 84112-5330, USA.
authors.forename: Jyoti R
authors.initials: JR
authors.lastname: Misra
authors.forename: Geanette
authors.initials: G
authors.lastname: Lam
authors.forename: Carl S
authors.initials: CS
authors.lastname: Thummel
mesh_terms: D000818:Animals; D001665:Binding Sites; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D007305:Insecticide Resistance / Q000235:genetics*; D007306:Insecticides / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D018384:Oxidative Stress / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D015398:Signal Transduction
chemical_list: D029721:Drosophila Proteins; D007306:Insecticides; D047908:Intracellular Signaling Peptides and Proteins; C527886:Keap1 protein, Drosophila; D000072019:Kelch-Like ECH-Associated Protein 1
keywords: Gene regulation; Insecticide resistance; Nrf2; Transcriptional control